Mechanistic Differences in Adult-Onset and Juvenile-Onset Huntington's Disease and the Potential Role of Neurodevelopment.

Huntington's disease (HD) is a progressive neurodegenerative disease that primarily affects the striatum and causes cognitive, motor, and psychiatric symptoms. HD onset before the age of 20 is considered juvenile-onset HD (JHD). This review explores the mechanisms and pathology of JHD, with a focus on how ongoing maturation of neural circuits could cause JHD to differ from adult-onset HD (AHD). We identify key mechanistic differences related to the polyglutamine expansion in the huntingtin (HTT) gene, transcriptional dysregulation and splicing errors in striatal neurons, dysregulation of synaptogenesis, behaviors of protein aggregates, and failure of proteostasis. We also briefly summarize differences in the disease burden, diagnostic necessities, and treatment options. Overall, there are significant mechanistic and symptomatic differences between AHD and JHD due to the developmental windows during which JHD occurs, and this review highlights the importance of understanding these differences for developing accurate, early diagnostic measures and implementing effective JHD-specific therapies.